Wound treatment containing collagen and a gelatin-reducing agent, and method for promoting wound healing

ABSTRACT

Disclosed is a wound treatment that includes collagen and a gelatin-reducing agent. Also disclosed is a wound dressing including a substrate, collagen, and a gelatin-reducing agent. The collagen and gelatin-reducing agent may be present in any suitable a weight ratio relative to one another, such as a weight ratio of about 0.25:1 to about 4:1 with respect to one another. Also disclosed is a method for promoting wound healing including administering collagen and a gelatin-reducing agent to a wound in need of treatment.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/587,844, filed Nov. 17, 2017, which is incorporated herein byreference in its entirety.

FIELD

The application relates generally to a wound treatment and a method forpromoting wound healing, particularly chronic wounds.

BACKGROUND

After an injury, including accidental or medically-induced injuries tothe skin or other affected tissue, the body undergoes a natural processto repair the damage. The wound repair process involves a complexcoordination of biochemical processes to remove damaged cells and tissueand to promote new tissue growth. Many wounds heal quickly with minimalmedical attention. For severe acute wounds, the healing process may bedelayed and may result in painful inflammation, infection, or scarring.Significant medical attention may be required for such wounds.Additionally, chronic wounds, such as pressure sores, diabetic footulcers, and arterial ulcers, generally require significant medicalattention. A variety of medical conditions may also complicate and slowthe healing process, including diabetes or diseases that cause poorblood circulation. In such cases, additional steps are desirably takento assist the natural wound healing process.

During the normal wound repair process, fibroblasts produce collagen,which is a structural protein that plays an important role in new tissuedevelopment. Fibroblasts are recruited to the wound site and collagenexpression is upregulated. In some wounds, such as chronic wounds, afailure or delay in fibroblast recruitment or collagen expression at thewound site can adversely affect wound healing. Chronic wounds may alsobe characterized by high matrix metalloprotease (“MMP”) levels. MMPscomprise a family of enzymes involved in the breakdown of theextracellular matrix. Of these, collagenases generally degrade intactcollagen, while gelatinases generally degrade denatured or damagedcollagen (i.e., gelatin). Necrotic tissue contains a high proportion ofdamaged collagen. Living tissue contains a higher proportion ofnon-degraded collagen. In general, intact collagen is a precursor ofdegraded gelatin.

MMPs generally play a helpful role in the early, inflammatory phase ofwound healing when they are essential to clean up loose, unanchoredcollagen (that role is played by collagenase MMPs) as well as degradedcollagen (that degradation or clean up role is played by the gelatinasetype of MMPs). However, excessive MMP levels or higher levels of someMMPs versus others, long after the acute inflammatory phase should havepassed, can inhibit the wound healing process by resulting inineffectually low collagen levels at the wound site. MMP levels areaffected, at least in part, by levels of other enzymes, such aselastase, which converts MMP precursors to active MMPs. Accordingly,high elastase levels in the wounds also promote faster collagenbreakdown and lower collagen levels at the wound site. Elastases alsobreak down a key protein elastin.

A major direct, as well as indirect, source of MMPs and otherproteinases are wound pathogens in necrotic tissue. High levels ofproteases result from a combination of related factors. First, themicrobes themselves secrete the degradative and inflammatory enzymes tocatabolize tissue and tissue associated substances (e.g., extracellularmatrix or “ECM” that contain collagen and gelatin) to provide nutritionfor themselves. Second, the high levels of bacteria associated withnecrotic tissue recruit cells of the innate immune system that secretethese proteinases on a continuous basis. In the delay of wound healingfor chronic wounds, the presence of necrotic tissue is a significantcause of these problems, and it is difficult to remove all of thenecrotic tissue using a surgical or other mechanical technique.

It has been reported that bacterial biofilms are associated with asignificant percentage of chronic wounds. The microbes associated withbiofilms are a significant source of MMP levels in chronic wounds. Thebiofilms become tolerant to antibiotic therapy and are difficult toeliminate. Studies have shown that surgical debridement can temporarilyremove biofilms but that biofilms can return within days. The presenceof biofilms leads to massive congregation of macrophages which areunable to physically penetrate the exopolymeric matrix and simply remainpersistent in the wound site and secrete inflammatory enzymes such asMMPs, which include collagenases and gelatinases. The former delayswound healing.

It also has been reported that tissue inhibitors of metalloproteinases(“TIMPs”) levels are generally slightly lower in chronic wounds than inacute wounds. Unchecked, MMPs can also result in the unwanteddestruction of beneficial proteins, such as growth factors, growthfactor receptors, and TIMPs, that are important for the healing process.

It is therefore generally desired to provide a composition and methodthat is effective to increase collagen levels while reducing gelatin atthe wound site, thereby promoting wound healing. It has been found thata wound treatment can comprise, in combination, collagen and agelatin-reducing agent. Preferably, at least a majority of the collagenis native collagen, and the gelatin-reducing agent is a poloxamer. Thewound treatment may take any suitable form, such as a wound dressing. Itis believed that collagen will interact with collagenases naturallypresent in the wound to preserve the collagen, thus inhibiting gelatinformation, and that the poloxamer or other gelatin-reducing agent willboth help to physically remove gelatin from the wound and to inhibitgelatin formation by one or more actions of potentiating gelatinases ordepotentiating collagenases in the wound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side view of a wound treatment dressing according to oneembodiment.

FIG. 2 is a side view of an alternative wound treatment dressing.

FIG. 3 is a side view of yet another alternative wound treatmentdressing.

DETAILED DESCRIPTION

Provided herein is a wound treatment comprising a gelatin-reducing agentand collagen. A method of promoting wound healing is also provided. Asdescribed in more detail below, the wound treatment may be applieddirectly to the wound, applied to a bandage or dressing that covers thewound, or re-suspended in solution and injected into the wound or itspenumbra to promote wound healing. The treatment is believed to resultin improved wound healing, which potentially can result in reduced pain,less scarring, and/or avoidance of other more invasive treatments, suchas skin grafting. The wound treatment provided herein alsoadvantageously addresses the problem of necrotic tissue removal andpromotes healing via the unique combination of collagen andgelatin-reducing agent.

The wound treatment may be administered to a variety of wounds,including wounds on the surface of the skin or internal wounds.Generally, the term “wound” includes any tissue or organ damaging orpenetrating injury, such as a cut, puncture, biopsy, bite wound,abrasion, contusion, laceration, incision or other surgical wound, orwound resulting from a firearm or explosive device. The term “wound”also includes thermal wounds (such as frostbite, sunburn, radiation, orburn caused by fire, intense heat, steam, or hot liquid) and chemicalwounds (such as from contact with a caustic chemical). Chronic woundsinclude, for example, pressure sores, diabetic foot ulcers, and arterialulcers.

Generally, the wound treatment comprises collagen and a gelatin-reducingagent. The term “gelatin-reducing agent” as used herein refers to agentsuseful in the wound treatments described herein, which are effective toreduce the amount of gelatin, and in some cases eliminate the amount ofgelatin, physically present at the wound site. The gelatin-reducingagent is a separate ingredient from the collagen or collagen derivativeused herein. In other words, for purposes herein, the collagen orcollagen derivative is not considered the gelatin-reducing agent, and asecond ingredient in the wound treatment is used to fulfill the role ofthe gelatin-reducing agent. The gelatin-reducing agent may act bydeactivating, sequestering, or otherwise reducing the activity ofcollagenase at the wound site, and/or to increase or otherwiseupregulate gelatinase activity in the wound. The gelatin-reducing agentmay also assist in physically removing gelatin from the wound site. Eachactivity individually has the effect of reducing the amount of gelatinphysically present and/or formed in the wound. In at least one approach,the gelatin-reducing agent is effective to both decrease collagenaseactivity and increase gelatinase activity. By reducing or otherwisesuppressing collagenase activity, which has little redeeming value inchronic wounds, and increasing gelatinase activity, which functions toremove necrotic tissue that itself delays wound healing (e.g., via thecycle of promoting bacterial growth, biofilm formation, immune cellingress and persistence, and chronicity), the net result is protectionof intact tissue and elimination of degraded necrotic tissue at thewound site.

It is believed that, as a general matter, collagen is desirable in thewound healing process. The natural healing process causes collagenasesto be generated in the region of a wound, and the collagenases cause theformation of necrotic tissue, which is principally gelatin or hydrolyzedcollagen. It is further believed that gelatinases cause degradation ofthe gelatin into small molecules, which exit the wound via naturalbiological processes. The introduction of collagen from an externalsource is believed to biologically interact with collagenases in thewound to inhibit hydrolysis of natural collagen produced in the wound.Patients with comorbidities, such as diabetes, tend to have moredifficulty generating natural collagen at the wound site. Therefore,there is a significant need to preserve the natural collagen produced ina patient who may be generally unwell with comorbid conditions. Thecollagen in the wound treatment may act as a sacrificial substrate forcollagenases in the wound. Introduced collagen in some cases may alsocause some non-catalytic binding of collagenases in the wound, therebyfurther making the collagenases less bioavailable for activity in thewound.

The collagen in the wound treatment may be provided in a variety offorms, including native collagen (“Type 1”) or denatured collagen (i.e.,collagen that has lost its triple helical structure). It is preferable,however, that at least a majority of the collagen (in another aspect atleast about 60 percent, and in another aspect at least about 75 percentof the collagen) should be present as native collagen, i.e., collagenthat has not been denatured. The collagen may be derived from a varietyof sources, including, for example, human (e.g., placental collagen),bovine, porcine, equine, or avian sources. In particular, anon-antigenic purified form of collagen may be used. Commerciallyavailable forms of collagen include, for example, PURACOL Plus Ultra(Medline, Inc.), which has native collagen structure. This has theeffect of reducing the amount of collagenase available to degradecollagen produced in the wound site, thereby stabilizing or increasingbeneficial collagen levels in the wound. In doing so, gelatin formation,and in turn de novo necrotic tissue formation, is advantageouslyreduced.

Any suitable gelatin-reducing agent may be employed. One particularlypreferred gelatin-reducing agent is a surfactant, by which iscontemplated a substance capable of reducing the surface tension of aliquid. In one particular approach, the gelatin-reducing agent iseffective to remove slough and necrotic tissue. Because degradedcollagen or gelatin may be loosely adherent to the wound bed, abiocompatible non-ionic surfactant capable of forming micelles may beused to sequester gelatin or gelatinous necrotic tissue and physicallyremove it from the wound. Suitable surfactants include, for example,glycolipids, phospholipids, ethoxy laces (such as poloxamers),poloxamines, and fatty acid esters such as glycerol monolaurate orTweens. In some embodiments, the gelatin-reducing agent comprises or isa poloxamer. Various poloxamers are commercially available, such as apoloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108,poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer 184, poloxamer185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217,poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, poloxamer238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer 331,poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338, poloxamer401, poloxamer 402, poloxamer 403 and poloxamer 407, or a combinationthereof. In one particular approach, the poloxamer comprises or ispoloxamer 188. Poloxamers are named with a three-digit number, where thefirst two digits multiplied by 100 indicate the molecular mass and thelast digit multiplied by 10 indicates the polyoxyethylene content.Commercially available PLURONIC® poloxamers may be obtained fromSigma-Aldrich or BASF Corporation. Poloxamer 188 is provided in theproduct PluroGel (available from Medline Industries). Poloxamer 188 isalso sold in powder or granular form as Kolliphor ® P 188 Micro (BASF).As noted above, microbes associated with biofilms are a significantsource of MMP levels in chronic wounds. Therefore, particularlypreferred gelatin-reducing agents for the wound treatment compositionsand methods described herein, such as poloxamer 188, are also effectiveto remove biofilms. Gelatin formation is indirectly reduced whenbiofilms are broken up and removed by the surfactant. Accordingly,particularly preferred surfactants are effective to physically removenecrotic tissue (e.g., via micelle carriers), suppress collagenaseactivity, amplify gelatinase activity, and degrade and remove biofilms.

Advantageously, the gelatin-reducing agents useful herein do not degradethe collagen included in the treatment. Therefore, the activity of thecollagen to suppress MMP activity can act in parallel with that of thegelatin-reducing agent. Also, the gelatin-reducing agents useful hereinare not deactivated by common wound healing agents, such asantimicrobial silver ions.

The wound treatment may be provided in a variety of forms, such as in apowder, gel, paste, cream, foam, wash, or other liquid form. The woundtreatment may also be formed into a film-like substrate. Liquidformulations of the wound treatment can be prepared, such as, forexample, in the form of a solution or suspension in a non-toxic,parenterally-acceptable solvent or diluent. In another approach, theformulation may be a powder or lyophilizate that is reconstituted in aliquid or other media of choice prior to use. In yet another approach,the wound treatment may be in the form of an emulsion or liquidconcentrate for dilution prior to administration. Exemplarypharmaceutically-acceptable carriers include saline, PEG, phosphatebuffered saline, isotonic saline, Ringer's solution, dextrose, sterilewater, deionized water, glycerol, ethanol, 5% dextrose in water, orother biocompatible liquid, and combinations thereof. For example, thewound treatment may be administered to the wound as a component of abioadhesive.

The wound treatment may also further comprise one or more additionalpharmaceutically acceptable components, such as to provide a desiredviscosity or tackiness to the composition. The wound treatment mayfurther include additional active agents, such as an antibiotic,antimicrobial (e.g., silver- or iodine-containing compounds),provitamin, antioxidant, vitamin, moisturizer, scar reducing agent, orother active agent known to promote wound healing. In one particularapproach, the wound treatment further comprises iodine.

The wound treatment can be stored, such as in sealed vials or ampules,for long periods of time and used on an as needed basis. Powdered orother “neat” wound treatments provide great flexibility to theapplications in which they may be used. For example, the composition inpowdered or granular form may be used upon hydration, reconstitution, orsuspension in liquid or other media before administration to a subject.The mixture may also be sterilized before being administered to thesubject. The wound treatment can also be administered to a subject inpowder or granular form and without reconstitution.

In one particular approach, the gelatin-reducing agent and collagen orcollagen derivative are provided in granular/powdered form and mixedtogether. In one approach, the collagen or collagen derivative may actas a vehicle for delivery of the gelatin-reducing agent.Pharmaceutically-acceptable solid excipients may also be included. Themixed powder is filled in vials. An appropriate quantity of fluid, suchas water, saline, or PEG, may be added to the vial and then the mixturecan be poured or dispensed via syringe into the wound to be treated.

The collagen and the gelatin-reducing agent may be present in anysuitable amounts relative to one another. For example, the woundtreatment may include collagen and gelatin-reducing agent in a weightratio of about 0.25:1 to about 4:1, or a ratio of about 0.5:1 to about2:1, or the ratio may range from 35:65 to 65:35, or may be about 1:1.

The wound treatment may take the form of a wound dressing that comprisesthe collagen and gelatin-reducing agent on a substrate. In oneembodiment, and as shown in FIG. 1, where the wound treatment is appliedto a substrate to form a wound dressing, dressing 100 comprises at leastone layer 102 and has a wound contacting surface 104 that would bepositioned adjacent the wound during wound treatment. The woundtreatment may be extruded, sprayed, sprinkled, laminated, or otherwiseapplied onto the layer 102. The wound treatment may be applied to thewound contacting surface 104 or non-wound contacting surface 106. Thesubstrate may be of cotton, nonwoven synthetic material, or any suitablesubstrate material. Generally, the collagen should be present in thewound dressing in an amount effective to reduce or inhibit woundcollagenase activity, and the gelatin-reducing agent should be presentin an amount effective to reduce or mitigate wound gelatin formation. Inone approach, the wound dressing may include up to about 5 grams ofcollagen and up to about 5 grams of gelatin-reducing agent per 100square centimeters of surface area.

In another embodiment and as shown in FIG. 2, dressing 200 comprises atleast two layers. Layer 202 is a wound contacting layer and has a woundcontacting surface 204. The dressing 200 further comprises layer 208.The wound treatment may be applied to wound contacting layer 202 orlayer 208. Optionally, there may be an adhesive layer 210 positionedbetween layer 202 and layer 208. The wound treatment may also be presentin a separate layer positioned between layer 202 and layer 208 inaddition to or instead of layer 210.

In yet another approach and as shown in FIG. 3, the dressing maycomprise at least one adhesive portion 310 and a wound contactingportion 312 (such as in the format of a bandage with two adhesiveportions separated by a wound contacting portion). The wound contactingportion 312 may comprise any of the configurations described herein,such as in dressing 100 or 200.

One or more of the layers of the dressing may include pores or otheropenings effective to allow moisture or other bodily fluid to pass fromthe wound to the wound treatment present in or on the dressing. One ormore of the layers may also have a minimum or maximum moisture vaportransmission rate, if desired. Any of the configurations describedherein may further comprise a non-absorbent layer, such as a top layer,that does not contact the wound and is moisture resistant or imperviousso as to contain any blood or other exudate from the wound. The one ormore layers of the dressing may include, for example, a polymer film,polyurethane foam, cellulose fiber, nonwoven fabric, woven fabric,paper, adhesive, or any combination thereof. The one or more layers mayalso include one or more additional active agents that have been appliedthereto.

The dressings provided herein may also be provided in a variety offorms, such as in the form of a sheet, patch, bandage pad, roll, or thelike. In this respect, the dressing may he in the form of an individualunit or as a larger unit that may be subdivided to provide smallerdressings, as needed. At least in some approaches, the dressing isflexible to permit the dressing to conform to the shape of the woundsite.

Also provided herein is a kit comprising collagen and a gelatin-reducingagent. For example, the collagen and gelatin-reducing agent may beprovided in powder form. The kit may further include liquid media forreconstituting, hydrating, or otherwise suspending the powdered collagenand gelatin-reducing agent. The kit may also include instructions formixing the collagen and gelatin-reducing agent in the media to form awound treatment and for applying the wound treatment to a wound. Ifdesired, the kit may further comprise bandages or other dressings.

Methods are also provided for promoting wound treatment comprisingadministering a therapeutically effective amount of collagen and agelatin-reducing agent to a wound of a subject. Promoting wound healingcomprises, for example, accelerating wound closure. Promoting woundhealing may also comprise removal of necrotic tissue or slough.

Prior to administering the collagen and a gelatin-reducing agent to thewound (either separately, together as a mixture, or together in the formof a wound dressing), the wound may be pretreated, such as by cleaningor debriding the wound. Open wounds may be infected and/or may includeforeign materials that may lead to infection or delay wound healing. Inparticular, pretreatment may be carried out to remove foreign materialsor infectious agents in or around the wound. Debridement may be carriedout to loosen and remove necrotic, infected, or other damaged tissue inthe wound in order to promote healing.

The method for cleaning or debriding the wound is not particularlylimited. Conventional wound cleaning or debriding treatments may beused, as needed, such as curettage or sharp debridement. Somedebridement techniques may encourage autolytic (e.g., enzymatic)debridement, such as by applying occlusive materials to the wound (e.g.,a medical grade polysaccharide such as honey). Collagenase enzyme isitself sometimes used to promote debridement, but application ofcollagenase may not be suitable within a certain amount of time beforeapplying the wound treatment provided herein because the collagen in thewound treatment may engage the collagenase used for debridement.Therefore, the collagenase would not be fulfilling the primary purposefor using it, namely to remove necrotic collagenous tissue. Also, if onefirst uses externally supplied collagenase to remove necrotic tissue toprepare the wound bed for a collagen dressing, and then later uses thecollagen dressing, this sequential treatment has lengthened the totaltime needed to achieve improved wound healing. Collagenase, suppliedexternally for debridement purposes, is also rendered ineffective withsilver ions, which are frequently present in the wound fromsilver-containing wound dressings.

In at least one approach, the method for promoting wound healingcomprises administering a wound treatment comprising collagen and agelatin-reducing agent to a wound of a subject in need of wound healing.The wound treatment is delivered to the wound in a therapeuticallyeffective amount to promote wound healing. While the collagen andgelatin-reducing agent may be delivered to the wound together or inshort succession (such as within five minutes), it is also contemplatedthat the collagen and gelatin-reducing agent may be administeredsequentially, preferably so that one is administered within about 30minutes of the other. This “parallel” mode of treatment allows for thegelatin-reducing agent and collagen to provide for faster wound healingby removing necrotic tissue removal and promoting wound healing at thesame time.

The method may further comprise covering the treated wound with aconventional wound dressing, gauze, or bandage, if desired. The methodmay further comprise preparing the wound treatment by mixing collagenand a gelatin-reducing agent with a pharmaceutically acceptable carrierprior to administering the wound treatment to the subject. If providedin powder or other solid form, the wound treatment may be hydrated priorto use, such as by addition of physiologically acceptable fluid to thewound treatment. In other approaches, the wound treatment may be appliedto the site of the wound in powder form, such that biological fluid atthe site of the wound is sufficient to solubilize the composition.

The wound treatment may be administered to the wound in any desirableroute, such as by topical administration or by irrigating the wound withthe composition. Administration may also be carried out by spraying,pouring, inserting (such as via a syringe), injecting, or dropping (suchas with a medicine dropper or pipette) the wound treatment onto thewound.

In the methods described herein, the wound treatment is delivered in aneffective amount to a damaged tissue in a subject in need of treatment.As used herein, the term “subject” includes mammals, such as but notlimited to rodents, pigs, cats, dogs, and primates, and specificallyincludes humans. The term “effective amount” or “therapeuticallyeffective amount” means the amount that will elicit the biological ormedical response of a subject that is being sought by a medical doctoror other clinician. In one aspect, the term “effective amount” isintended to mean the amount that will bring about a biologicallymeaningful improvement in the wound.

Data obtained from animal studies can be used in formulating a range ofdosages for human use. The dosage may vary depending upon the dosageform employed, sensitivity of the patient, and the route ofadministration. The dosage suitable for a given subject can bedetermined by one of skill in the art. Generally, dosage andadministration can be adjusted to provide or to maintain the desiredeffect. The optimal dose of collagen and gelatin-reducing agent maydepend, at least in part, on the severity of the wound and method ofdelivery.

The treatment regimen can vary depending on the particular needs of thesubject. For example, the dose and frequency of administration maydepend in part on the size or severity of the wound. By way ofnon-limiting illustration, the wound treatment may be applied at leastonce daily. Some subjects may benefit from more frequent application ofthe composition. In one approach, the collagen may be applied from dailyto weekly, and the gelatin-reducing agent may be applied from daily toabout once every three days.

It is thus seen that a wound treatment may be provided and used inaccordance with the foregoing teachings.

As used herein, all percentages are by weight unless stated otherwise.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or language describing anexample (e.g., “such as”) provided herein, is intended to illuminate theinvention and does not pose a limitation on the scope of the invention.Any statement herein as to the nature or benefits of the invention or ofthe preferred embodiments is not intended to be limiting. This inventionincludes all modifications and equivalents of the subject matter recitedherein as permitted by applicable law. Moreover, any combination of theabove-described elements in all possible variations thereof isencompassed by the invention unless otherwise indicated herein orotherwise clearly contradicted by context. The description herein of anyreference or patent, even if identified as “prior,” is not intended toconstitute a concession that such reference or patent is available asprior art against the present invention. No unclaimed language should bedeemed to limit the invention in scope. Any statements or suggestionsherein that certain features constitute a component of the claimedinvention are not intended to be limiting unless reflected in theappended claims. Neither the marking of the patent number on any productnor the identification of the patent number in connection with anyservice should be deemed a representation that all embodiments describedherein are incorporated into such product or service.

What is claimed is:
 1. A wound treatment comprising, in combination,collagen and a gelatin-reducing agent.
 2. The wound treatment accordingto claim 1, wherein at least a majority of the collagen is nativecollagen.
 3. The wound treatment according to claim 1 or claim 2,wherein the agent comprises a surfactant.
 4. The wound treatmentaccording to claim 3, wherein the surfactant comprises a poloxamer. 5.The wound treatment according to claim 4 wherein the poloxamer comprisesone or more of poloxamer 101, poloxamer 105, poloxamer 105 benzoate,poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer181, poloxamer 182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215,poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288,poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer338, poloxamer 401, poloxamer 402, poloxamer 403 or poloxamer
 407. 6.The wound treatment according to claim 4, wherein the poloxamercomprises poloxamer
 188. 7. The wound treatment according to any one ofclaims 4 to 6, the collagen and poloxamer being present in a ratio withrespect to one another ranging from 35:65 to 65:35 collagen:poloxamer.8. A wound dressing comprising: a substrate having a wound contactinglayer; collagen; and a gelatin-reducing agent; the collagen beingpresent in said dressing in an amount effective to reduce woundcollagenase activity, and the gelatin-reducing agent being present in anamount effective to reduce wound gelatin formation.
 9. The wounddressing according to claim 8, wherein at least a majority of thecollagen is native collagen.
 10. The wound dressing according to claim 8or 9, wherein the gelatin-reducing agent comprises a surfactant.
 11. Thewound dressing according to claim 10, wherein the surfactant comprises apoloxamer.
 12. The wound dressing according to claim 11, wherein thepoloxamer comprises one or more of poloxamer 101, poloxamer 105,poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123,poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 182 dibenzoate,poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234,poloxamer 235, poloxamer 237, poloxamer 238, poloxamer 282, poloxamer284, poloxamer 288, poloxamer 331, poloxamer 333, poloxamer 334,poloxamer 335, poloxamer 338, poloxamer 401, poloxamer 402, poloxamer403 or poloxamer
 407. 13. The wound dressing according to claim 11,wherein the poloxamer comprises poloxamer
 188. 14. The wound dressingaccording to any one of claims 11 to 13, the collagen and poloxamerbeing present in a ratio with respect to one another ranging from 35:65to 65:35 collagen:poloxamer.
 15. A method for promoting wound healing ina subject, the method comprising administering collagen and agelatin-reducing agent to a wound, the collagen being administered in anamount effective to reduce wound collagenase activity, and thegelatin-reducing agent being administered in an amount effective toreduce wound gelatin formation.
 16. The method according to claim 15,wherein the collagen and gelatin-reducing agent are administeredsequentially.
 17. The method according to claim 15, wherein the collagenand gelatin-reducing agent are administered together as a mixture. 18.The method according to claim 15, wherein the collagen andgelatin-reducing agent are administered to the wound as part of adressing comprising a substrate having a wound contacting layer;collagen; and a gelatin-reducing agent; the collagen being present insaid dressing in an amount effective to reduce wound collagenaseactivity, and the gelatin-reducing agent being present in an amounteffective to reduce wound gelatin formation.
 19. The method according toany one of claims 13 to 16, wherein at least a majority of the collagenis native collagen.
 20. The method according to any one of claims 13 to17, wherein the agent comprises a surfactant.
 21. The method accordingto any one of claims 20, wherein the surfactant comprises a poloxamer.22. The method according to claim 21, wherein the poloxamer comprisesone or more of poloxamer 101, poloxamer 105, poloxamer 105 benzoate,poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer181, poloxamer 182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215,poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer237, poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288,poloxamer 331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer338, poloxamer 401, poloxamer 402, poloxamer 403 or poloxamer
 407. 23.The method according to claim 21 or 22, wherein the poloxamer comprisespoloxamer
 188. 24. A wound treatment comprising, in combination,collagen and a surfactant.
 25. The wound treatment according to claim24, wherein the surfactant comprises a poloxamer.
 26. The woundtreatment according to claim 25, wherein the poloxamer comprises one ormore of poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181,poloxamer 182, poloxamer 182 dibenzoate, poloxamer 183, poloxamer 184,poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237,poloxamer 238, poloxamer 282, poloxamer 284, poloxamer 288, poloxamer331, poloxamer 333, poloxamer 334, poloxamer 335, poloxamer 338,poloxamer 401, poloxamer 402, poloxamer 403 or poloxamer
 407. 27. Thewound treatment according to claim 25, wherein the poloxamer comprisespoloxamer
 188. 28. The wound treatment according to any one of claims 24to 26, wherein the collagen and surfactant are present in a weight ratioof about 0.25:1 to about 4:1 with respect to each other.
 29. The woundtreatment according to claim 27, wherein the collagen and poloxamer 188are present in a weight ratio of about 0.25:1 to about 4:1 with respectto each other.
 30. The wound treatment according to any one of claims 24to 29, wherein at least a majority of the collagen is native collagen.31. The wound treatment according to any one of claims 1 to 7 or 24 to30, wherein the wound treatment is in powder form.